Certain 1-acyl derivatives of 7-alkoxy-2,3,4,5-tetrahydro-1h-1-benzazepine



United States Patent 3,458,498 CERTAIN l-ACYL DERIVATIVES (9F '7-ALKOXY-2,3,4,5-TETRAHYDRfi-lH-1-BENZAZEPHNE Charles NI. C. Koo, Philadelphia,and Thomas W. Pattison and David R. Herhst, King of Prussia, Pa.,assignors to American Home Products orporation, New York, N.Y., acorporation of Delaware No Drawing. Filed Apr. 25, 1966, Ser. No.544,681

Int. Cl. C07c 41/08; Alk 27/00 US. 'Cl. 260239 5 Claims ABSTRACT OF THEDISCLDSURE This invention concerns 7-alkoxy-1-carboxamido-2,3,4,S-tet-rahydro-lH-l-benzazepines which are pharmacologically etficaciousas diuretic, hypoglycemic, anti-bacterial and anticonvulsant agents.

This invention relates to bicyclic nitrogen containing compounds knownas benzazepines. In particular, the invention is concerned with7-alkoxy-2,3,4,5-tetrahydro-1H- l-benzazepines having pharmacologicalactivity.

The novel compounds which are included within the scope of thisinvention are represented by the following formula:

2, 3,4,5 -tetrahydro-7-methoxy- 1 H- l-benzazepine;

1-acetyl-2,3 ,4,5-tetrahydro-7-methoxy- 1H- 1 -benzazepine;

1- (4-chlorobenzoy1) -2,3,4,5 -tetrahydro-7-methoxy-1H- 1- benzaze pine2,3 ,4,5-tetrahydro-7-methoxy-1- (4-tolylsulfonyl) 1H-1- benzazepine;

1- cyclohexycarbamoyl -2,3 ,4,5-tetrahydro-7-methoxylH-l -benzazepine;and

2, 3,4,5 -tetrahydro-7-methoxy- 1-( phenylthiocarbamoyl)lH-l-benzazepine.

The benzazepine compounds of the present invention are prepared by thefollowing schematic sequence of reactions:

lRoduction Patented July 29,, 1969 ice wherein R and R are defined asabove. Reduction of the 4-[(Z-amino-S-alkoxy)phenyl] butyric acid,lactam (I) may be effected by reaction with a reducing agent. Preferablythis reaction is conducted in dioxane with lithium aluminum hydrideunder gentle reflux. Thereafter, the excess lithium aluminum hydride isdecomposed with a dilute aqueous solution of an alkali metal hydroxideand the resulting 7-alkoxy 2,3,4,5 tetrahydro-IH-l-benzazepine (II) isseparated by conventional recovery procedures such as, filtration,concentration and crystallization.

The 7 alkoxy 2,3,4,5 tetrahydro-l-substituted-1H-1- benzazepines (III)of the present invention are prepared by admixing an above prepared7-alkoxy-2,3,4,5-tetrahydro-lH-l-benzazepine (II) base with asubstantially equimolar amount of an appropriate aliphatic acid; analiphatic acid halide or anhydride; a cycloalkanoyl or aroyl halide; analkyl or aryl sulfonyl halide; an alkyl, cycloalkyl, alkenyl or aroylisocyanate; or an alkyl, alkenyl, cycloalkyl or aroyl isothiocyanate ina reaction-inert organic solvent at a temperature range from about 25 C.to about C. for a period of about ten minutes to about five hours, Whenthe reaction is complete, the ap propriate7-alkoxy-2,3,4,S-tetrahydro-l-substituted-lH-lbenzazepine (III) isobtained by standard methods well known to those skilled in the chemicalart, e.g., dilution, extraction, concentration and crystallization.

The time and temperature ranges utilized in the above mentionedreactions are not critical and simply represent the most convenientranges consistent with carrying out the reaction in a minimum of timewithout undue difficulty. Thus, reaction temperatures appreciably belowthese can be used, but their use considerably extends the reaction time.Similarly, reaction temperatures higher than those mentioned can beemployed with a concomitant decrease in reaction time. By reaction-inertorganic solvent is meant any organic solvent which dissolves thereactants and does not interfere with their interaction. The amount ofsolvent used is not critical, it being only necessary to use sufficientsolvent to provide a reaction medium for the reactants.

Many of the reactants employed to prepare the compounds of thisinvention are known compounds which are available from commercialsources, while the remainder can be prepared in accordance with standardorganic procedures well known to those skilled in the art. The4-[(Z-amino-S-alkoxy)phenyl] butyric acid, lactams are prepared from thecorresponding 6-alkoxytetralones by the procedure of G. Schroeter, Chem.Ber., 63, 1324 (1930).

In accord with the present invention, the compounds of the presentinvention have been found to possess interesting pharmaceuticalproperties which render them useful as synthetic medicinals. Moreparticularly, these compounds, in standard pharmacological tests, haveexhibited 3 utility as diuretics, hypoglycemics, anti-bacterials andanticonvulsants. Further, the 7-alkoxy-2,3,4,5-tetrahydr0-1H-l-benzazepines (II) are used as intercmediates in the preparation of the7-alkoxy-2,3,4,5-tetrahydro-l-substituted-lH-lbenzazepine (III)compounds of this invention.

When the compounds of this invention are employed as diuretics,hypoglycemics, anti-bacterials and anti-convulsants, they may 'beadministered alone or in combination with pharmaceutically acceptablecarriers, the proportion of which is determined by the solubility andchemical nature of the compound, chosen route of administration andstandard pharmaceutical practice. For example, they may be administeredorally in the form of tablets or capsules containing such excipients asstarch, milk, sugar, certain types of clay and so forth. They may beadministered sublingually in the form of troches or lozenges in whichthe active ingredient is mixed with sugar and corn syrups, flavoringagents and dyes; and then dehydrated suificiently to make it suitablefor pressing into a solid form, They may be administered orally in theform of solutions which may contain coloring and flavoring agents orthey may be injected parenterally, that is intramuscularly,intravenously or subcutaneously. For parenteral administration they maybe used in the form of a sterile solution containing other solutes, forexample, enough saline or glucose to make the solution isotonic.

The dosage of the present therapeutic agents will vary with the form ofadministration and the particular compound chosen. Furthermore, it willvary with the particular subject under treatment. Generally, treatmentis initiated with small dosages substantially less than the optimum doseof the compound. Thereafter, the dosage is increased by small incrementsuntil the optimum effect under the circumstances is reached. It willgenerally be found that when the composition is administered orally,larger quantities of the active agent will be required to produce thesame effect as a smaller quantity given parenterally. In general, thecompounds of this invention are most desirably administered at aconcentration level that will generally afford effective results withoutcausing any harmful or deleterious side effects and preferably at alevel that is in the range of from about 25 mg. to about 1000 mg. perday, although as aforementioned, variations will occur. However, adosage level that is in the range of from about 75 mg. to about 400 mg.per day is most desirably employed in order to achieve effectiveresults.

The following examples are given by way of illustration and are not tobe construed as limitations of this invention, many variations of whichare possible without departing from the scope and spirit thereof.

EXAMPLE I A solution of 10 g. 4-[(2-amino-5-methoxyl)phenyl] butyricacid, lactam in 100 ml. of dioxane is added to a stirred suspension of2.98 g. 95% lithium aluminum hydride in 100 ml, dioxane such that gentlereflux is maintained. After one hour of refluxing, the reaction mixtureis cooled, cautiously treated with 15 ml. 3% w./v. aqueous sodiumhydroxide and filtered. The insolubles are thoroughly washed with etherand the combined organic fractions are freed of solvent. Dissolution ofthe oily residue in 2 N hydrochloric acid, washing of the acidicsolution with ether followed by basification with potassium carbonate,extraction with ether and removal of the solvent aiford2,3,4,5-tetrahydro-7-methoxy-lH-l-benzazepine as an oil. This base isdissolved in ether and treated with excess hydrogen chloride to form thehydrochloride salt which, after two recrystallizations from nitromethaneexhibits, M.P. 204.5207.0 C., LEE; 3.75, 3.99, 4.10,, 71 230 (6 7,760),275.5 (e 1,280), 282 (e 1,410) m Analysis for C H NO-HCl.Ca1cd.: C,61.81; H, 7.55; Cl, 16.59; N, 6.56. Found: C, 61.66; H, 7.54; Cl, 17.10;N, 6.57.

EXAMPLE II A solution of 2,3,4,5-tetrahydro-7-methoxy-1H-l-benzazepine(generated by basification of an aqueous solution of 5.34 g. of thehydrochloride, prepared in Example I, with aqueous sodium hydroxide andextraction with ether), 50 ml. pyridine and 3.87 g. benzoyl chloride(3.17 ml.) is kept at 25 C. for seventeen hours. Dilution of thereaction solution with ice-water, thorough extraction with etherfollowed by successive washings of the extracts with dilute hydrochloricacid, dil. aqueous potassium bicarbonate, brine and drying (sodiumsulfate) and distillation of the solvent yield crude amide. Tworecrystallizations of this product from acetone-n-hexane afford1-benzoyl-2,3, 4,5-tetrahydro-7-methoxy-1H-1-benzazepine, MP. 134- 136C.,

KB max The following compounds are prepared in this manner by treating2,3,4,5-tetrahydro 7 methoxy-1H-1-benzazepine with an appropriatebenzoyl chloride:

1-(4-tbromobenzoyl)-2,3,4,5-tetrahydro-7-methoxy-1H-1- benzazepine;

1-(3-iodobenzoy1)-2,3,4,5-tetrahydro-7-methoxy-1H-1- benzazepine;

2,3 ,4,5-tetrahydro-7-methoxy- (4-propylbenzoyl -lH-1- benzazepine;

1- (4-fluorobenzoyl) -2,3,4,5-tetrahydro-7-methoxy- 1H- 1- benzazepine;

1- (2-ethy1benz0yl -2,3,4,5-tetrahydro-7-methoxy-1H-1- benzazepine; and

1-(4-eth-oxybenzoy1)-2,3,4,5-tetrahydro-7-methoxy-1H-1- benzazepine.

EXAMPLE III Repeating the procedure of Example II to react 2,3,4,5-tetrahyd-ro-7-methoxy-lH-l-benzazepine with the hereinafter listedreactants, the following products are obtained.

Reactant Product M.P., C. is h (ii) ti anhydride 1i-acety1-2,3,4,5-tetrahydro-7-methoxy-lH-l-benzazepine.--. 80-83n-Hexane 05 Pivaloyl chloride 12,3,4,zi-tetrahydro-7-methoxy-l-pivaloyl-IH-l-lmuzazepiue.- 72.5-75.0 do6. 15 Cyclopropanecarbonyl chloride-1-gcfigggllcgrbonyl)-2,3,4,5-tetrahydro-7-mcthoxy-1H- 62.63 do ,11Cyclopentaneearbonyl chloride 2 1-gygfigg icgrbonyi)-2,3,4,5-tetrahydr0-7-methoxy-1H- 57- .---.do 6.11 ccloliexanccarbonyl chloride 2 l-gzs c lggigylcarbonyl)-2,3,4.b-tetrahydrofl-methoxy-lH-l- 69- do 6.08 p-Chlorobenzoylchloride 1-gi glgzggoggoylyzaaetetrahydr0-7-me h0Xy-1H-1- 70- -.--.do6.10 p-Toluoyl chloride2,3,4,5-tetrahydro-7-methoxy-1-(4-t01u0y1)-lH-l-benza- 78-81 do 6.11Anisoyl chloride l-( igiiisoyl)-2,3,4,5-tetrahydro-7-methoxy-1H-1-bcnza- 107. 5110.0Acetonc-n-hexane, 6.15 3,4,5-trlmethoxybeuzoy1chloride ze grif i h o gnethoxy-is,4,strimethoxybenzoyi)- 109-112 do 6.12p-Chlorobenzencsuiionyl chloride 11-(filciizggazlgggliiilfonyl)-2,3,4,5-tctrahydro-7-methoxy- 132. 5-134.0 Ethyl acetate 7. 46, 8. 63 p-Toluenesulionyl chloride 2%:h5Z-ZZErS-iI1I1SdIO-7-met OXY-I-(4-ii0ly Su1IonyD-1H-1 128-130 Methanol 7. 47, 8.

1 The extraction solvent is chloroform.

2 The crude product is chromatographicaily purified on neutral, activityIII alumina prior to recrystallization.

EXAMPLE IV Similarly, the following compounds are produced:

1-(4-butylsulfonyl)-2,3,4,5-tetrahydro-7-meth0xy-1H-1- benzazepine;

1-(4 bromophenylsulfonyl) 7 ethoxy-2,3,4,5-tetrahydro-lH-l-benzazepine;and

1 (4 ethoxyphenylsulfonyl) 2,3,4,5 tetrahydro 7-propoxy-lH-l-benzazepine.

EXAMPLE V A solution of 2,3,4,5 tetrahydro 7 methoxy-lH-lbenzazepine(generated by basification of an aqueous solution of 10.00 g. of thehydrochloride with aqueous potassium hydroxide and extraction withether), 50 ml. pyridine and 8.27 g. of benzenesulfonylchloride areadmixed and stirred for twenty-four hours at 25 C. Dilution of thereaction solution with ice-water, thorough extraction with etherfollowed by successive washings of the extracts with dilute hydrochloricacid, dil. aqueous potassium bicarbonate, brine and drying (sodiumsulfate) and distillation of the solvent yield the crude product. Tworecrystallizations of this product from acetone-nhexane yield 2,3,4,5-tetrahydro-7-methoxy-l-(phenylsulfonyl)-1H-1-benzazepine, M.P. 124126C.,

Similarly, 2,3,4,5-tetrahydro-1-(2-inodophenylsulfonyl)- 7-propoxy 1H 1benzazepine and 1-(4-butoxyphenylsulfonyl)-2,3,4,5-tetrahydro 7methoxy-lH-l-benzazepine are produced.

EXAMPLE VI A solution of 2,3,4,5-tetrahydro-7-methoxy-lH-l-benzazepine(20.0 g.), 200 ml. pyridine and 12.9 g. of methanesulfonyl chloride areadmixed with stirring for seventeen hours at 25 C. Thereafter, thereaction mixture is admixed with ice-water, extracted with etherfollowed by successive washings of the extracts with dilute hydrochloricacid, dil. aqueous potassium bicarbonate, brine and drying (sodiumsulfate). Distillation of the solvent yields crude product. Tworecrystallizations of this product from acetone-n-hexane yield2,3,4,5-tetrahydro 7 methoxy 1 (methylsulfonyl)-1H-1-benzazepine, M.P.84-85 0.,

In the same manner, 7 ethoxy 1(p-ethylphenylsulfonyl)-2,3,4,5-tetrahydro 1H 1 benzazepine andl-(pfluorophenylsulfonyl) 2,3,4,5 tetrahydro 7 propoxylH-l-benzazepineare obtained.

EXAMPLE VII Reflux 2,3,4,5-tetrahydro 7 methoxy-lH-l-benzazepine(prepared from 16.03 g. of the hydrochloride) with 50 ml. 98% formicacid for three and a half hours. Thereafter, the reaction mixture isadmixed with ice-water and extracted with ether. The combined extractsare washed with dilute hydrochloric acid, brine and dried (sodiumsulfate). Evaporation of the solvent and crystallization of the residuefrom ether-n-hexane and from carbon tetra- EXAMPLE VIII To 8.55 g.2,3,4,5-tetrahydro-7-methoxy-lH-l-benzazepine, hydrochloride in 50 ml.methanol is added 2.16 g. sodium methoxide. The mixture is stirred forfive minutes, filtered and the filtrate is freed of solvent byevaporation. Drying of the base thus prepared is achieved by additionand distillation of 50 m1. toluene. Thereafter, the dry amine isrefluxed with 4.17 g. n-butyl isocyanate (4.80 ml.) and 75 ml. benzenefor two hours. After removal of the benzene, the residue is dissolved inchloroform, washed with dilute hydrochloric acid, brine and dried(sodium sulfate). Evaporation of the chloroform and tworecrystallizations of the residue from ether-n-hexane yieldl-(butylcarbamoyl) 2,3,4,5 tetrahydro-7-methoxy-1H- l-benzazepine, M.P.6668 C.,

max.

EXAMPLE IX To 4.28 g. 2,3,4,5-tetrahydro-7-methoxy-lH-l-benzazepine,hydrochloride in 25 ml. methanol is added 1.08 g. sodium methoxide. Themixture is stirred five minutes, filtered and the filtrate evaporated.Drying of the base thus prepared is achieved by addition anddistillation of 25 ml. toluene, and the dry amine is refluxed with 3.0g. phenyl isocyanate and 75 ml. benzene for three hours. After removalof the benzene, the residue is dissolved in chloroform, washed withdilute hydrochloric acid, brine and dried (sodium sulfate). Evaporationof the chloroform and two recrystallizations of the residue fromacetone-n-hexane yield 2,3,4,5-tetrahydro-7-methoxy-1- (phenylcarbamoyl)-.1H 1 benzazepine, M.P. 146.5- 148.5 C.,

max.-

EXAMPLE X The procedure described in Examples VIII and IX is repeatedreacting a 7-alkoxy-2,3,4,5-tetrahydro-lH-lbenzazepine with anappropriate hereinafter listed isocyanate to produce the followingbenzazepines:

Reactants Products 2,3,4,5-tetrahydro7-methoxy-IH-lbenzazepine andcyclopentyl isocyanate.

7-ethoxy-2,3,4,5-tetrahydro-1H-1- benzazepine and methyl isocyanate.2,3,4,5-1:etrahydro-7-methoxy-1H-1- benzazepine and p-tolyl isoeyanate.2,3,4,5-tetrahydro-7-propoxy-1H-1- benzazepine and Isa-methoxyphenylisocyanate. 3,4,5-tetrahydro-7-methoxy-lH-l- 2,benzazep1ne and pethylphenyl isocyanate. 2,3,4,5-tetrahydro-7-methoxy-1H-1- benzazepmeand p-butylphenyl isocyanate.2,3,4,5-tetrahydro-7-methoxy-lH-lbenzazepine and p-propoxyphenylisocyanate.

1-(cyclopentyloarbamoyl)-2,3,4,5-

tetrahydro-7-methoxy-1H-1- bonzazepine. 7-ethoxy-2,3,4,5-tstrahydro-1-(methylcarbamoyl)-1H-1-benzazepine. 2,3,4,5-tetmhydro-7-methoxy-1-(p-tolylcarbamoyl)-1H-1-benzazepine.2,3,4.5-tetrahydro-1-(in-methoxyphenylcarbamoyl)-7-propoxylH-I-benzazepine.1-(p-ethylphenylcarbamoyl)- 2,3.4,5-tetrahydro7-methoxylH-l-benzazepine.1-(p-bntylphenylcarbamoyl)- 2,3,4.5tetrahydro-7-methoxylH-l-benzazepine.2,3,4,5-tetrahydro-7-methoxy-1- (p-propoxyphenylcarbamoyl)-1H-1-benzazep1ne.

EXAMPLE XI the chloroform and two recrystallizations of the residue fromether-n-hexane yield l-(cyclohexylcarbamoyl)-2,3,

7 4,5 -tetrahydro-7-methoxy-1H-l-benzazepine, M.P. 70- 73 C.,

A335; 3.06, 6.11 Similarly,

I- (p-chlorophenylcarbamoyl -2,3,4,5-tetrahydro-7-methoxy-1H-l-benzazepine;

1-(p-bromophenylcarbarnoyl)12,3 ,4,5-tetrahydro-7-methoxylH-l-benzazepine and 7-ethoxy-2,3 ,4,5-tetrahydro- 1-(p-iodophenylcarbamoyl lH-l-benzazepine are prepared.

EXAMPLE XII A mixture of 10.68 g., 2,3,4,5-tetrahydro-7-methoxylH-l-benzazepine hydrochloride, 250 ml. absolute ethanol and 2.70 g. sodiummethoxide is stirred at 25 C. for fifteen minutes. Allyl isothiocyanate(5.21 g., 5.13 ml.) is added, the mixture is refluxed four hours, andthen the solvent is distilled. A benzene extract of the residue iswashed with dilute hydrochloric acid, brine, dried (sodium sulfate),freed of solvent and the crude product is triturated with n-hexane andtwice recrystallized from isopropanol. In this manner, is obtainedl-(allylthiocarbamoyl) 2,3,4,5 tetrahydro 7 methoxy 1H 1- benzazepine,M.P. 9l94 C.,

Similarly, the following compounds are prepared: 1-(Z-butenylthiocarbamoyl) 2,3,4,5-tetrahydro-7- methoxy-1H-l-benzazepine;2,3,4,5-tetrahydro-7-metl1oxy-1-(methylthiocarbamoyl)- lH-l-benzazepine;and 1-(isobutylthiocarbamoyl)-2,3,4,5-tetrahydro-7-methoxy-lH-l-benzazepine.

EXAMPLE XIII max. 3

EXAMPLE XIV Employing the procedure of Example XIII reacting a 7 alkoxy2,3,4,5 tetrahydro-IH-l-benzazepine with an appropriate phenylisothiocyanate, the hereinafter listed benzazepines are obtained:

7-ethoxy-2,3,4,S-tetrahydro-l-(p-tolylthiocarbarnoyl)- lH-l-benzazepine;

1-(m-butylphenylthiocarbamoyl)-2,3,4,5-tetrahydro-7- methoxy-lH-l-benzazepine;

2,3,4,5-tetrahydro-1- (p-methoxyphenylthiocarbamoyl)-7-methoxy-lH-l-benzazepine;

1- (p-ethoxyphenylthiocarb amoyl) -2,3,4,5-tetrahydro-7-propoxy-lH-l-benzazepine;

2,3,4,5-tetrahydro-7-methoxy- 1- (p-propoxyphenylthiocarb amoyl-1H-1-benza'zepine;

1- (p-chlorophenylthiocarbamoyl -7-butoxy-2,3 ,4,5-

tetrahydro-lH- l-benzazepine;

1- (o-bromophenylthiocarbamoyl) -2,3,4,5-tetrahydro-7- methoxy-lH-l-benzazepine;

2,3 ,4,5-tetrahydro-l-(p-iodophenylthiocarbamoyl -7methoxy-lH-l-benzazepine; and

7 -ethoxy- 1- p-fluorophenylthiocarb amoyl -2,3 ,4,5-

tetrahydro- 1H- l-benzazepine EXAMPLE XV A mixture of 10.0 g.,2,3,4,5-tetrahydro-7-methoxy-1H- l-benzazepine hydrochloride, 250 ml.absolute ethanol and 2.6 g. sodium methoxide is stirred at 25 C. for onehalf hour. Cyclohexylisothiocyanate (6.6 g.) is added, the mixture isrefluxed five hours, and then the solvent is distilled. A benzeneextract of the residue is washed with dilute hydrochloric acid, brine,dried (sodium sulfate), freed of solvent and the crude product istriturated with n-hexane and twice recrystallized from acetone-nhexaneto yield 1-(cyclohexylthiocarbamoyl)-2,3,4,5- tetrahydro-7-methoxy-lH-l-benzazepine, M.P. -98 C.,

In the same manner, 1-(cyclobutylthiocarbamoyl)-2,3,4,5-tetrahydro-7-methoxy-l-H-l-benzazepine is produced.

What is claimed is:

1. A compound selected from the group consisting of those having theformula:

wherein R is selected from the group consisting of lower alkanoyl,cyclo(lower)alkylcarbonyl, benzoyl, halobenzoyl, lower alkylbenzoyl,lower alkoxybenzoyl and lower polyalkoxybenzoyl; and R is lower alkyl.

2. A compound as described in claim 1 which is: 1-acetyl-2,3,4,5-tetrahydro-7-methoxy-lH-l-benzazepine.

3. A compound as described in claim 1 which is: 1-(cyclopentylcanbonyl)-2,3,4,5-tetrahydro 7 methoxylH-l-benzazepine.

4. A compound as described in claim 1 which is: 1- benzoyl-2,3,4,5tetrahydro-7-meth0xy-lH-l-benzazepine.

5. A compound as described in claim 1 which is: 1-(4- chlorobenzoyl)2,3,4,5 tetrahydro 7 methoxy 1H- l-benzazepine.

References Cited Bell et al., J. Chem. Soc. (London), pp. 4926-4930(1964).

ALTON D. ROLLINS, Primary Examiner US. Cl. X.R. 260239.3; 424244

